Tissue defects are sometimes repaired with porous scaffolds comprising biocompatable materials. The porous nature of the devices allows the inward migration of cells, followed by the in-growth of tissue, thereby repairing the defect. The pore structure must be controlled to ensure optimal inward cell migration (e.g., sized large enough to accommodate cells, and avoid altering the cell phenotype), from which the new tissue may form. Current devices do not adequately control pore geometry, size, and distribution, with processes that are economically attractive. Additionally, open porous networks facilitate cell migration throughout the implant, thereby speeding up regeneration. Also, mechanical properties of existing porous structures are less than desirable for applications where the implant is subjected to post implant stresses. The porous nature also minimizes the amount of foreign material placed into the patient.
Most processes for producing porous biomaterial implants utilize a leaching method wherein a leachable substance such as sodium chloride is mixed with a biomaterial such as polymethylmethacrylate (PMMA) and later removed with a solvent such as water. U.S. Pat. No. 4,199,864 (Ashman), U.S. Pat. No. 4,636,526, (Dorman et al), and U.S. Pat. No. 5,766,618 (Laurencin et al), describe such methods. Such leaching methods are time consuming and in many instances only a portion of the leachable substance is effectively removed from the implant.
Other processes for creating porous medical implants utilize a vacuum freezing operation as described in U.S. Pat. No. 6,306,424 (Vyakarnam, et al), U.S. Pat. No. 5,766,618 (Laurencin et al), and U.S. Pat. No. 5,133,755 (Brekke). These processes are not generally suited to mass production and often utilize non-biocompatable solvents.
A “plasticized melt-flow” process (PMF) has been developed, in an effort to increase the strength, and reduce costs, of molded polymeric parts. Such a process is described in U.S. Pat. No. 6,169,122 (Blizard et al) and U.S. Pat. No. 6,231,942 (Blizard et al) and by David Pierick and Kai Jacobsen, “Injection Molding Innovation: The Microcellular Foam Process,” Plastics Engineering, May 2001, pp 46–51 (such disclosures being incorporated herein by reference). In general, such a process uses a gas (e.g., N2, or CO2) under high pressures to create a supercritical fluid (SCF). The SCF, when depressurized, liberates the gas, thereby creating a porous structure.
The pores in the PMF processes noted above are nucleated by nucleating agents which are added in the range of 2 to 7 percent. As a result the pores may be more homogeneously dispersed through the molded part, than pores seen in other processing methods known in the art. The Pierick-Jacobsen paper reports that the aim of this technology is reducing costs, through the reduction of polymer used and decreasing cycle time, i.e., nucleating agent takes the place of matrix polymer, thereby reducing the amount of polymer needed.
The process is proposed for use in various industrial components (e.g., car mirror housings, ink and Laserjet printer parts), no medical applications, procedures, or devices are disclosed.
A CESP process (Controlled Expansion of Saturated Polymers), however, has been contemplated for use in manufacturing implantable polymer structures by Pfannschmidt, et al, “Production of Drug-Releasing Resorbable Polymer Stents with Foam Structure”, Medical Plastics Technology News, Fall 1999-Winter 1999–2000, pp 10–12. The focus of the paper is the use of CESP for the incorporation of “thermally sensitive additives.” These additives are suggested to include proteins and growth factors. The devices proposed to deliver these additives are stents. No structural or load-bearing applications are disclosed. In fact, the focus of the invention is the low temperature processability of the invention, however, the resulting process is not readily mass producible.
The CESP may be useful for the delivery of those agents because of the low temperature employed in the CESP process; that is, as previously mentioned, the temperature is not raised to create flow, but rather the pressure is. Therefore, additives may be used that would not survive the temperature of traditional high-temperature molding techniques. However, the CESP process additionally does not adequately address the problem of satisfactory tissue ingrowth or regeneration.
The need for higher strengths in porous polymers has previously been recognized, as in U.S. Pat. No. 6,169,122 (Blizard, et al), where the process is controlled to minimize the cell (i.e., porosity) growth. The aim of the invention is to create homogeneously distributed pores, of a small size (i.e., preferably below 50 microns). To this end, nucleation aids (e.g., talc and titania) are added to the polymer, in an effort to nucleate a larger number of pores during the decompression step (as previously described). However, this paper does not contemplate the problem of satisfactory tissue ingrowth or regeneration, since it strives to create pores that may not be of suitable size to cause effective cellular differentiation and reproduction.
These approaches to utilizing PMF and CESP types of processes for creating porous polymers, for the repair of tissue, would fall short of what is needed in existing surgical procedures. Higher strengths are paramount for implants that may need to withstand any loading following implant; additionally, some implant products (e.g., screws) require continuing strength to withstand the procedural stress. However, proper cell migration into the implant structure, in most cases, require pores on the order of 100 to 250 microns. Therefore, decreasing the pore size below about 100 microns—while increasing strength—could actually prohibit proper cell ingress.
Additionally, talc or titania nucleation aids may not be suited for certain cellular environments, and may further deter cell ingress, or damage or alter normal cellular function and differentiation if such cells were to infiltrate the implant.
The PMF and CESP processes, as disclosed above, creates pores that typically do not communicate with each other. This isolation slows and potentially prevents the continued ingress of cells, through the entire implant cross section, which may delay tissue development, and/or restrict tissue development to the regions at or near the surface of the implant.
Additionally, the closed cell pores of the PMF process do not address the concerns of heterogeneous degradation that occur in massive biodegradable implants. Hydrolysis is not an erosion phenomenon for most biodegradable polymers, but is, instead, a bulk process with random hydrolytic scission of covalent ester bonds. The correlation of in vivo and in vitro rates of hydrolysis has led to the theory that degradation is not facilitated by enzymatic catalysis, or at least not during the initial loss of molecular weight. Hydrolysis is affected by many factors including crystallinity, molecular weight, polydispersity, sterilization process, geometry of the device, total surface area exposed to interstitial fluid, sight of implantation, etc. Although many functions affect biodegradation, hydrolysis has generally been identified to proceed in four main steps i.e., hydration, strength loss, structural integrity loss, and mass loss.
The closed cell pores of the PMF and CESP processes may exasperate problems associated with heterogeneous degradation by providing multiple isolated chambers separated by a thin membrane. These thin membranes may expedite the movement of body fluids deep into the implant where they may pool for a prolonged period of time isolated from interstitial turnover.
In addition, the pores produced by these, and similar, processes typically have uniform or smooth surfaces between the matrix juncture (similar to that of honeycomb structures). Even if these processes were able to yield pores with open architectures, the smooth walls would not be conducive to cell attachment.
Accordingly, there exists a need for homogenous, mass-producible, higher strength, resorbable implants with large pores. The pores may be modeled (i.e., the surfaces made rough or irregular) or intercommunicating and/or foster cell attachment. Embodiments of the current invention address these and other shortcomings in the prior art.